In developing animals, blockade of angiotensin II actions results in delayed nephrogenesis and arrested renal vascular development. Similarly, adult mice with targeted deletions of the angiotensincoverting enzyme (ACE) or angiotensinogen (Ao) genes develop concentric-obstructive arterial lesions, glomerular and interstitial sclerosis and tubular dilatation resembling end-stage nephrosclerotic kidney disease. Our recent observations indicate that these abnormalities start in early life and are accompanied by hypertrophy and hyperplasia of renin-expressing cells in renal arterioles and in the renal interstitium. We hypothesize that in the absence of angiotensin: 1) there is an altered developmental program in the formation of arterioles and nephrons, 2) differentiation of renal cells is impaired, and 3) metaplastic renin- expressing cells contribute to and/or stimulate uncoordinated, disorganized concentric growth of renal vascular and interstitial cells resulting in vascular obstruction and architectural disorganization of the kidney. Mice with altered copy numbers of the ACE and Ao genes will be used to 1) define the ontogeny and evolution of kidney abnormalities, 2) define the lineage and identity of the cells participating in aberrant nephronvascular growth, 3) determine whether angiotensin peptides can prevent or rescue the kidney abnormalities and 3) determine whether (and when) metaplastic renin-expressing cells are responsible for abnormal nephrovascular growth. These studies should generate fundamental knowledge regarding renal cell differentiation, and vascular growth and remodelling in the absence of angiotensin. By generating a new mouse model in which renin-expressing cells can be ablated at different periods of life, the proposed experiments should provide new strategies for our understanding of nephrovascular growth, hypertension and kidney diseases.